Pain resulting from nerve injury is often refractory to standard analgesics, like narcotics and pain-relieving procedures. Common neuropathic pain syndromes include deafferentation pain, diabetic, cancer and ischemic neuropathies, phantom limb pain, trigeminal neuralgia, postherpetic neuralgias and nerve injury caused by surgery or trauma. Neuropathic pain is typically chronic, intractable and debilitating causing extreme physical, psychological and social disruption in the quality of life for the patient. The broad, long-term objective of our research is to elucidate the mechanisms responsible for the generation and maintenance of neuropathic pain. This will enable the development of new pain medications that are effective in these pain syndromes and have limited abuse liability. Our laboratory has recently developed a novel mononeuropathy rat model using a freeze lesion, termed sciatic cryoneurolysis (SCN). This model is distinct from other neuropathic pain models by the presence of a biphasic nociceptive process; the early phase of limited autotomy may involve abnormal peripheral regeneration, while the later, prolonged mechanical allodynia may be indicative of spinal hyperactivity. The role of immune responses and cytokine (growth factor) production in the origin and maintenance of neuropathic pain is presently unknown. The hypothesis that both a peripheral regenerative nerve component and a central/spinal hypersensitivity generate neuropathic pain via growth factor changes is tested through the following specific aims: l) Temporally characterize spinal growth factors after two different types of nerve injury in the rat that produce neuropathic pain behaviors; 2) Determine the effect of acute intraneural or intrathecal basic Fibroblast Growth Factor (FGF) and anti-Transforming Growth Factor-b1 (TGF) on behavior in normal rats; and 3) Determine the effect of intraneural or intrathecal Anti-FGF or TGF in the attenuation of neuropathic pain behaviors in rats. Quantitative immunocytochemistry and nociceptive behavioral as says will be used to address these specific aims. With these studies completed, we will have: 1) information on the time course of spinal expression of two growth factors following a complete, but temporary peripheral nerve injury (SCN rat model) and a partial nerve injury (Chronic Constriction Injury rat model) which both produce neuropathic behaviors; 2) data on the possible hyperalgesic effects of FGF and TGF; 3) preliminary data to support potential new pharmacological treatments of neuropathic pain; 4) a foundation for understanding the neuroimmune response of peripheral nerve injury and the relationship to the production of chronic pain; and 5) preliminary data to guide future studies to evaluate the role of cytokines and neuroimmune responses in neuropathic pain.